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2014 ; 289
(47
): 32895-913
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Sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) is a novel nucleotide
phosphodiesterase regulated by cholesterol in human macrophages
#MMPMID25288789
Traini M
; Quinn CM
; Sandoval C
; Johansson E
; Schroder K
; Kockx M
; Meikle PJ
; Jessup W
; Kritharides L
J Biol Chem
2014[Nov]; 289
(47
): 32895-913
PMID25288789
show ga
Cholesterol-loaded foam cell macrophages are prominent in atherosclerotic lesions
and play complex roles in both inflammatory signaling and lipid metabolism, which
are underpinned by large scale reprogramming of gene expression. We performed a
microarray study of primary human macrophages that showed that transcription of
the sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) gene is up-regulated
after cholesterol loading. SMPDL3A protein expression in and secretion from
primary macrophages are stimulated by cholesterol loading, liver X receptor
ligands, and cyclic AMP, and N-glycosylated SMPDL3A protein is detectable in
circulating blood. We demonstrate for the first time that SMPDL3A is a functional
phosphodiesterase with an acidic pH optimum. We provide evidence that SMPDL3A is
not an acid sphingomyelinase but unexpectedly is active against nucleotide
diphosphate and triphosphate substrates at acidic and neutral pH. SMPDL3A is a
major source of nucleotide phosphodiesterase activity secreted by liver X
receptor-stimulated human macrophages. Extracellular nucleotides such as ATP may
activate pro-inflammatory responses in immune cells. Increased expression and
secretion of SMPDL3A by cholesterol-loaded macrophage foam cells in lesions may
decrease local concentrations of pro-inflammatory nucleotides and potentially
represent a novel anti-inflammatory axis linking lipid metabolism with purinergic
signaling in atherosclerosis.